Role of histotripsy synergized CD40 signaling in the re-engineering of cold tumors

项目摘要 晚期转移性黑色素瘤是最致命的皮肤癌，通常对化疗和 放射治疗。对于这类患者来说，免疫检查点抑制剂(Icis)的出现是一场革命性的变革。 改变，提高肿瘤缓解率和存活率，扭转以前缺乏进展的局面。尽管前景看好，但一个 很大比例的患者，特别是那些免疫原性较差的(“冷”)肿瘤患者，仅表现出适度的 对ICIS的反应，甚至应答者经常复发。新的肿瘤重组技术迫在眉睫 需要提高免疫抗药性感冒肿瘤患者的存活率。这个项目的目标是 优化一种基于局部聚焦超声组织旅行(HT)和抗肿瘤治疗的创新组合疗法 CD40激动剂抗体(ACD40)包裹聚合物微粒(CMPS)重编程冷性黑色素瘤 肿瘤。在实体癌中，HT以非侵入性方式快速产生边界清晰的脱细胞抗原库， 而aCD40则激活抗原提呈细胞(APC)。我们对小鼠黑色素瘤的研究发现， 与单用可溶性aCD40相比有效，与ICI/HT联合应用可实现完全缓解 未经治疗的肿瘤。基于这一前提，我们将检验肿瘤内给药的中心假设 具有捕获肿瘤抗原和与羟色胺持续激活CD40双重功能的中医将实现 局部治疗和远程未经治疗的黑色素瘤的持久缓解。为了检验我们的假设，目的是 1)测定联合化疗方案对免疫原性不同的小鼠肿瘤模型的疗效 和负荷，2)阐明了推动HT和CMP非局部效应的ICI耐药性逆转机制， 3)将我们的发现转化为对患有自发性恶性黑色素瘤的狗兽医患者的临床试验。 狗黑色素瘤类似于人类黑色素瘤，具有侵袭性转移，有利于 评估我们的组合疗法的可译性。将免疫上的“冷”肿瘤转化为 晚期癌症的免疫原性是一个具有挑战性的目标。项目成果将使快速 局部产生可与CD40协同的大型肿瘤抗原库激活冷黑色素瘤 发出信号以提高对局部治疗和远处未治疗肿瘤的疗效。我们在临床上的研究- 相关模型将提供提高大部分转移性黑色素瘤患者存活率的可行性 与免疫治疗抗药性肿瘤有关。

Project Summary Advanced-stage metastatic melanoma is the deadliest form of skin cancer, typically resistant to chemo- and radiotherapy. For such patients, the advent of immune checkpoint inhibitors (ICIs) has been a revolutionary change, improving tumor remission and survival rates, reversing prior lack of progress. Although promising, a large proportion of patients, especially those with poorly immunogenic ("cold") tumors, show only modest response to ICIs, and even responders relapse frequently. New tumor-reengineering technologies are urgently needed to improve survival rates in patients with immunoresistant cold tumors. The objective of this project is to optimize an innovative combinatorial therapy based on local focused ultrasound-based histotripsy (HT) and anti- CD40 agonist antibody (aCD40) encapsulated polymeric microparticles (CMPs) to reprogram cold melanoma tumors. HT non-invasively and rapidly generates acellular antigen depots with sharp boundaries in solid cancers, while aCD40 activates antigen-presenting cells (APCs). Our murine melanoma studies found that CMP is more efficacious compared to soluble aCD40 alone, and when combined with ICI/HT achieves complete remission of untreated tumors. Based on this premise, we will test the central hypothesis that intratumorally-administered CMPs that serve the dual functions of tumor antigen capture and sustained CD40 activation with HT will achieve durable remission of locally-treated and remote untreated melanomas. To test our hypothesis, the aims are to 1) Determine efficacy of the HT and CMP combined regimen in murine tumor models varying in immunogenicity and burden, 2) Elucidate ICI resistance reversal mechanisms that drives abscopal effects with HT and CMP, and 3) translate our findings to clinical trials in dog veterinary patients with spontaneous malignant melanoma. Dog melanoma resembles human melanoma, and metastasizes aggressively, and is advantageous for assessing translatability of our combinatorial therapy. Transforming immunologically “cold” tumors to immunogenic ones in advanced stages of cancer is a challenging goal. The project results will enable rapid activation of cold melanomas by locally generating large tumor antigen depots that can synergize with CD40 signaling to improve efficacy against locally treated and distant untreated tumors. Our studies in clinically- relevant models will inform feasibility of improving survival in a large proportion of metastatic melanoma patients with immunotherapy-resistant tumors.